Bioprosthetic device and methods of making the same

Abstract

A bioprosthetic device includes a frame and a bioprosthetic tissue including collagen and a plurality of holes. The bioprosthetic tissue is attached to the frame. The bioprosthetic device includes a plurality of sutures extending through the plurality of holes. In aspects, a periphery of the plurality of holes has a greater collagen cross-linking density or elastic modulus than a bulk of the bioprosthetic tissue. The bioprosthetic device can be a prosthetic heart valve assembly. Alternatively, a collagen-containing scaffold can have predetermined location with has a greater collagen cross-linking density or elastic modulus than a bulk of the collagen-containing scaffold. Methods include applying a cross-linking agent to a predetermined location. Methods further include cross-linking collagen at the predetermined location by impinging the predetermined location\ with a light beam, but a majority of a surface area of the bioprosthetic tissue does not have collagen cross-linked by the impinging.

Description

BIOPROSTHETIC DEVICE AND METHODS OF MAKING THE SAME

[0001] This application claims the benefit of priority under 35 U.S.C. § 119 of U.S. Provisional Application Serial No. 63 / 568043 filed March 21, 2024, the content of which is relied upon and incorporated herein by reference in its entirety.FIELD

[0002] The present disclosure relates generally to bioprosthetic device and methods comprising the same, and, more particularly, to a prosthetic heart valve apparatus having a bioprosthetic tissue including collagen and methods of making the same.BACKGROUND

[0003] It is known to provide a prosthetic heart valve assembly for implanting a heart valve prosthesis within a target site of the vasculature of a patient. The heart valve prosthesis can be moved from a radially-contracted position to a radially-expanded position.

[0004] It is known to attach bioprosthetic tissue to a frame of the prosthetic heart valve assembly using sutures. However, the prosthetic heart valve assembly can be damaged, for example, when sutures pull-out from the bioprosthetic issue as a result of handling or even ordinary wear and tear. Damaged prosthetic heart valve assembly can cause serious health consequences and require expensive medical procedures to replace the prosthetic heart valve assembly. Consequently, there is a need to improve the suture pull-out resistance of bioprosthetic tissue used in bioprosthetic devices, including prosthetic heart valve assemblies.SUMMARY

[0005] The following presents a simplified summary of the disclosure to provide a basic understanding of some aspects described in the detailed description.

[0006] There is set forth herein bioprosthetic tissue (e.g., as part of a bioprosthetic device) with increased mechanical properties and / or cross-linking density of collagen at one or more predetermined locations as well as methods of making the same (e.g., selectively crosslinking the collagen in the bioprosthetic tissue). The one or more predetermined locations can correspond to locations where there are holes in the bioprosthetic tissue, for example, where the bioprosthetic tissue is sutured to the rest of the bioprosthetic device (e.g., frame). Providing increased cross-linking density, increased elastic modulus, increased shear modulus, and / or increased acoustic velocity at and / or near a hole in the bioprosthetic tissue (e.g., corresponding to a location of a suture) at the one or more predetermined locations relative to the correspondingproperties of the bulk of the bioprosthetic tissue and / or corresponding bioprosthetic device to suture pull-out. In aspects, regions at the one or more predetermined locations with the increased properties can be surrounded by an intermediate region with properties intermediate between that at the one or more predetermined locations and the bulk of the bioprosthetic tissue, which can further improve resistance to suture pull-out, for example, by smoothing a transition between the properties at the one or more predetermined locations and the bulk of the bioprosthetic tissue. Providing the increased mechanical properties can enable the bioprosthetic tissue to closely mimic the properties of biological tissue in the bulk while improving the resistance to suture pull-out at the one or more predetermined locations corresponding to locations of a plurality of sutures. Also, methods of the present disclosure selectively cross-link collagen in the bioprosthetic tissue at the one or more predetermined by applying a cross-linking agent and then activating the cross-linking agent by impinging the crosslinking agent with an optical wavelength that the cross-linking agent is sensitive to.

[0007] In aspects, a bioprosthetic device comprises a frame and a bioprosthetic tissue comprising collagen comprising a plurality of holes. The bioprosthetic tissue can be attached to the frame. A plurality of sutures can extend through the plurality of holes. A periphery of the plurality of holes can have a greater collagen cross-linking density than a bulk of the bioprosthetic tissue.

[0008] In aspects, a bioprosthetic device comprises a frame and a bioprosthetic tissue comprising collagen comprising a plurality of holes. The bioprosthetic tissue can be attached to the frame. A plurality of sutures can extend through the plurality of holes. A periphery of the plurality of holes can have a greater elastic modulus than a bulk of the bioprosthetic tissue.

[0009] In aspects, a method of selectively cross-linking bioprosthetic tissue comprises applying a cross-linking agent to one or more predetermined locations of the bioprosthetic tissue comprising collagen. Methods further comprise cross-linking collagen at the one or more predetermined locations by impinging the one or more predetermined locations with a light beam. The light beam comprises an optical wavelength that the cross-linking agent is sensitive to. A majority of a surface area of the bioprosthetic tissue may not comprise collagen cross-linked by the impinging.

[0010] Additionally or alternatively, an increasing gradient (including smooth, continuous, and / or stepwise increase) in cross-linking density and / or mechanical properties can formed in a bioprosthetic tissue and / or a collagen-containing scaffold. Providing the increasing gradient in cross-linking density and / or mechanical properties can facilitate migration of cells up the increasing gradient of the collagen-containing scaffold and / or increased colonization of cells at or near the maximum of the increasing gradient. Further, the increased migration of cells alongthe increasing gradient and / or increased coloni gradient can provide further increases in mechanical properties, biocompatibility, and / or longevity of the resulting material (e.g., bioprosthetic tissue formed from colonization of the collagen-containing scaffold). Indeed, bioprosthetic tissue can be formed by cell colonization of a collagen-containing scaffold having the increasing gradient in cross-linking density and / or mechanical properties, where this increasing gradient would still be present in the resulting bioprosthetic tissue.

[0011] Additional features and advantages of the aspects disclosed herein will be set forth in the detailed description that follows, and in part will be clear to those skilled in the art from that description or recognized by practicing the aspects described herein, including the detailed description which follows, the claims, as well as the appended drawings. It is to be understood that both the foregoing general description and the following detailed description present aspects intended to provide an overview or framework for understanding the nature and character of the aspects disclosed herein. The accompanying drawings are included to provide further understanding and are incorporated into and constitute a part of this specification. The drawings illustrate various aspects of the disclosure, and together with the description explain the principles and operations thereof.BRIEF DESCRIPTION OF THE DRAWINGS

[0012] These and other features, aspects and advantages are better understood when the following detailed description is read with reference to the accompanying drawings, in which:

[0013] FIG. 1 schematically illustrates example aspects of a transcatheter heart valve prosthesis in accordance with aspects of the disclosure;

[0014] FIG. 2 illustrates a top-down view of the transcatheter heart valve prosthesis in accordance with aspects of the disclosure;

[0015] FIG. 3 illustrates a side view of a delivery assembly for delivering the transcatheter heart valve prosthesis in accordance with aspects of the disclosure;

[0016] FIG. 4 illustrates a side view of the delivery assembly for delivering the transcatheter heart valve prosthesis in accordance with aspects of the disclosure;

[0017] FIG. 5 illustrates an introducer sheath in accordance with aspects of the disclosure;

[0018] FIG. 6 illustrates an introducer sheath in accordance with aspects of the disclosure;

[0019] FIG. 7 illustrates a side view of a bioprosthetic heart valve with sutures shown in accordance with aspects of the disclosure;

[0020] FIG. 8 illustrates a bottom view of the bioprosthetic heart value of FIG. 7;

[0021] FIG. 9 illustrates a side view < shown in accordance with aspects of the disclosure;

[0022] FIG. 10 schematically illustrates a step of dispensing a cross-linking agent to a bioprosthetic tissue comprising collagen in accordance with aspects of methods;

[0023] FIG. 11 illustrates a schematic view of collagen taken along line 11-11 of FIG. 10;

[0024] FIG. 12 illustrates a schematic view of a bioprosthetic tissue comprising collagen and having a hole being stretched in accordance with aspects of methods;

[0025] FIG. 13 illustrates a impinging one or more predetermined locations of the bioprosthetic tissue with a light beam to cross-link collagen in accordance with aspects of methods;

[0026] FIG. 14 schematically illustrates cross-linked collagen in a bioprosthetic tissue, for example, corresponding to the bioprosthetic tissue shown in FIG. 11 after methods of the disclosure;

[0027] FIG. 15 schematically illustrates cross-linked collagen in a bioprosthetic tissue with the cross-linking localized around the hole, for example, corresponding to the bioprosthetic tissue shown in FIG. 12 after methods of the disclosure; and

[0028] FIG. 16 schematically illustrates a collagen-containing scaffold and / or bioprosthetic tissue where the cross-linking density increases going towards a predetermined location.DETAILED DESCRIPTION

[0029] Aspects will now be described more fully hereinafter with reference to the accompanying drawings in which example aspects are shown. Whenever possible, the same reference numerals are used throughout the drawings to refer to the same or like parts. However, this disclosure may be embodied in many different forms and should not be construed as limited to the aspects set forth herein.

[0030] As used herein, the term “about” means that amounts, sizes, formulations, parameters, and other quantities and characteristics are not, and need not be, exact, but may be approximate and / or larger or smaller, as desired, reflecting tolerances, conversion factors, rounding off, measurement error and the like, and other factors known to those of skill in the art.

[0031] Ranges can be expressed herein as from “about” one value, and / or to “about” another value. When such a range is expressed, aspects include from the one value to the other value. Similarly, when values are expressed as approximations by use of the antecedent “about,” it will be understood that the value forms another aspect. It will be further understood that theendpoints of each of the ranges are signific independently of the other endpoint.

[0032] Directional terms as used herein - for example up, down, right, left, front, back, top, bottom, upper, lower, etc. - are made only with reference to the figures as drawn and are not intended to imply absolute orientation.

[0033] Unless otherwise expressly stated, it is in no way intended that any methods set forth herein be construed as requiring that its steps be performed in a specific order, nor that with any apparatus, specific orientations be required. Accordingly, where a method claim does not actually recite an order to be followed by its steps, or that any apparatus claim does not actually recite an order or orientation to individual components, or it is not otherwise specifically stated in the claims or description that the steps are to be limited to a specific order, or that a specific order or orientation to components of an apparatus is not recited, it is in no way intended that an order or orientation be inferred in any respect. This holds for any possible non-express basis for interpretation, including matters of logic relative to arrangement of steps, operational flow, order of components, or orientation of components; plain meaning derived from grammatical organization or punctuation, and; the number or type of aspects described in the specification.

[0034] As used herein, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to “a” component includes aspects having two or more such components, unless the context clearly indicates otherwise.

[0035] The word “exemplary,” “example,” or various forms thereof are used herein to mean serving as an example, instance, or illustration. Any aspect or design described herein as “exemplary” or as an “example” should not be construed as preferred or advantageous over other aspects or designs. Furthermore, examples are provided solely for purposes of clarity and understanding and are not meant to limit or restrict the disclosed subject matter or relevant portions of this disclosure in any manner. It can be appreciated that a myriad of additional or alternate examples of varying scope could have been presented but have been omitted for purposes of brevity.

[0036] As used herein, the terms “comprising,” “including,” and variations thereof shall be construed as synonymous and open-ended, unless otherwise indicated. A list of elements following the transitional phrases comprising or including is a non-exclusive list, such that elements in addition to those specifically recited in the list may also be present.

[0037] The terms “substantial,” “substantially,” and variations thereof as used herein are intended to represent that a described feature is equal or approximately equal to a value or description. For example, a “substantially planar” surface is intended to denote a surface that isplanar or approximately planar. Moreover, “su are equal or approximately equal. The term “substantially” may denote values within about 10% of each other, for example, within about 5% of each other, or within about 2% of each other.

[0038] Modifications may be made to the instant disclosure without departing from the scope or spirit of the claimed subject matter. Unless specified otherwise, “first,” “second,” or the like are not intended to imply a temporal aspect, a spatial aspect, an ordering, etc. Rather, such terms are merely used as identifiers, names, etc. for features, elements, items, etc. For example, a first end and a second end generally correspond to end A and end B or two different ends.

[0039] Unless otherwise indicated, the terms “distal” and “proximal” are used in the following description with respect to a position or direction relative to the treating clinician. “Distal” and “distally” are positions distant from or in a direction away from the clinician, and “proximal” and “proximally” are positions near or in a direction toward the clinician. In addition, the term “self-expanding” may be used in the following description with reference to one or more valve or stent structures of the prostheses hereof and is intended to convey that the structures are shaped or formed from a material that can be provided with a mechanical memory to return the structure from a compressed or constricted delivery configuration to an expanded deployed configuration or vice versa. Non-exhaustive exemplary self-expanding materials include stainless steel, a pseudo-elastic metal such as a nickel-titanium alloy or nitinol, various polymers, or a so- called super alloy, which may have a base metal of nickel, cobalt, chromium, or other metal. Mechanical memory may be imparted to a wire or stent structure by thermal treatment to achieve a spring temper in stainless steel, for example, or to set a shape memory in a susceptible metal alloy, such as nitinol. Various polymers that can be made to have shape memory characteristics may also be suitable for use in aspects hereof include polymers such as polynorborene, transpolyisoprene, styrene-butadiene, and polyurethane. As well poly L-D lactic copolymer, oligo caprolactone copolymer, and poly cyclo-octine can be used separately or in conjunction with other shape memory polymers.

[0040] Diseases associated with heart valves, such as those caused by damage or a defect, can include stenosis and valvular insufficiency or regurgitation. For example, valvular stenosis causes the valve to become narrowed and hardened which can prevent blood flow to a downstream heart chamber from occurring at the proper flow rate and may cause the heart to work harder to pump the blood through the diseased valve. Valvular insufficiency or regurgitation occurs when the valve does not close completely, allowing blood to flow backwards, thereby causing the heart to be less efficient. A diseased or damaged valve, which can be congenital, age-related, drug-induced, or in some instances, caused by infection, can result in an enlarged, thickened heart that loses elasticity and efficiency. Some symptoms of heart valvediseases can include weakness, shortness of bi edema, and blood clots which can increase the likelihood of stroke or pulmonary embolism. Symptoms can often be severe enough to be debilitating and / or life-threatening.

[0041] The present disclosure related generally to bioprosthetic devices including bioprosthetic tissue comprising collagen. Example aspects of such bioprosthetic devices include stents and prosthetic heart valve assemblies, including surgical prosthetic heart valve assemblies as well as transcatheter heart valve assemblies. Prosthetic heart valve assemblies can be configured to replace the function of the mitral valve, the tricuspid valve, the pulmonary valve, or the aortic valve. While transcatheter heart valve assemblies (e.g., replacing the functionality of the aortic valve) are discussed below, it is to be understood that this is exemplary and the locally increased collagen cross-linking density, locally increased elastic modulus, locally increased acoustic velocity, etc. and associated methods of forming the same are applicable to bioprosthetic devices including all prosthetic heart valve assemblies generally. Also, bioprosthetic tissue includes autologous tissue, xenograft material, or cultured tissue or other synthetic tissue as long as the bioprosthetic tissue includes collagen (e.g., fibrils).

[0042] Heart valve prostheses have been developed for repair and replacement of diseased and / or damaged heart valves. Such heart valve prostheses can be percutaneously delivered and deployed at the site of the diseased heart valve through catheter-based delivery systems. Such heart valve prostheses generally include a frame or stent and a prosthetic valve mounted within the frame. Such heart valve prostheses are delivered in a radially compressed or crimped configuration so that the heart valve prosthesis can be advanced through the patient’s vasculature. Once positioned at the treatment site, the heart valve prosthesis is expanded to engage tissue at the diseased heart valve region to, for instance, hold the heart valve prosthesis in position.

[0043] FIGS. 1-2 illustrate an example transcatheter heart valve prosthesis 10. The delivery assemblies described herein may be used with the transcatheter heart valve prosthesis 10 and / or other transcatheter heart valve prostheses. The transcatheter heart valve prosthesis 10 is illustrated to facilitate description of the disclosure. The following description of the transcatheter heart valve prosthesis 10 is merely exemplary in nature and is not intended to limit the invention or the application and uses of the invention.

[0044] FIGS. 1 -2 illustrate a side view and a top (outflow end) view, respectively, of the transcatheter heart valve prosthesis 10. The transcatheter heart valve prosthesis 10 includes a radially-expandable frame 15 and a prosthetic valve 20. The frame 15 of the transcatheter heart valve prosthesis 10 supports the prosthetic valve 20 within an interior of the frame 15. In the example transcatheter heart valve prosthesis 10 shown in FIGS. 1 and 2, the frame 15 is self-expandable. However, this is not meant to expandable or mechanically expandable in other aspects.

[0045] The prosthetic valve 20 includes at least one leaflet 21 disposed within and secured to the frame 15. In the aspect shown in FIGS. 1 and 2, the prosthetic valve 20 includes exactly three leaflets 21, as shown in FIG. 2. However, this is not meant to be limiting, as the prosthetic valve 20 may include more or fewer leaflets 21. The leaflets 21 open and close to regulate flow through the transcatheter heart valve prosthesis 10. As discussed below with reference to FIGS. 7-8, a plurality of sutures 723 and 801 can be used to attach (e.g., secure) the one or more leaflets 21 the frame 15.

[0046] As shown in FIG. 1, the transcatheter heart valve prosthesis 10 includes an inflow end 11 and an outflow end 12. The leaflets 21 are attached to the frame 15 at commissures 25 such that when pressure at the inflow end 11 exceeds pressure at the outflow end 12, the leaflets 21 open to allow blood flow through the transcatheter heart valve prosthesis 10 from the inflow end 11 to the outflow end 12. When the pressure at the outflow end 12 exceeds pressure at the inflow end 11, the leaflets 21 close to prevent blood flow from the outflow end 12 to the inflow end 11. Accordingly, the at least one leaflet (e.g., the leaflets 21) can be attached to the plurality of struts 16, for example, by being directly attached to the plurality of struts 16 at the commissures 25, or by being indirectly attached to the plurality of struts 16, for example, by being attached to a skirt, a commissure bracket, or other structure (e.g., mechanical actuator) that is attached to the plurality of struts 16.

[0047] The frame 15 of the transcatheter heart valve prosthesis 10 further includes a plurality of struts 16 that are arranged to form a plurality of cells such as the first cells 18 and / or access cells 14 arranged circumferentially around a longitudinal axis LA of the transcatheter heart valve prosthesis 10 and longitudinally to form a tubular structure defining a central lumen 13 of the transcatheter heart valve prosthesis 10. For example, the frame 15 can extend along the longitudinal axis LA between the inflow end 11 and the outflow end 12. The frame 15 is configured to secure the prosthetic valve 20 within the central lumen 13 of the frame 15 and to secure the transcatheter heart valve prosthesis 10 in place in the vasculature of the patient. The struts 16 are defined herein as the elongated wire segments of the frame 15. Struts 16 come together to form crowns 17 or nodes 19, as can be seen in FIG. 1. The frame 15 of the transcatheter heart valve prosthesis 10 includes a plurality of cells (e.g., first cells 18, access cells 14) defined as the spaces between the plurality of crowns 17, the plurality of nodes 19, and the plurality of struts 16. The frame 15, and, thus, the plurality of struts 16, can be adjustable between a radially-collapsed position and a radially-expanded position.

[0048] In the example aspect shown ii shaped. In the example aspect shown, the plurality of cells include a plurality of first cells 18 and access cells 14. In particular, the access cells are larger than the first cells 18 and can provide access to one or more coronary arteries when the transcatheter heart valve prosthesis 10 is implanted in the patient. In the aspect shown, there are exactly three access cells 14. However, this is not meant to be limiting, as the frame 15 of the transcatheter heart valve prosthesis 10 can include more, fewer, or no access cells 14. The access cells 14 each have an enlarged area relative or compared to the first cells 18, as can be seen in FIG. 1. Further, the access cells 14 may be located in other locations than the locations shown in FIG. 1. Although not shown, in some aspects, the transcatheter heart valve prosthesis 10 may include an outer skirt (see outer skirt 721 and / or inner skirt 711 in FIG. 7 and / or skirt 931 shown generally in FIG. 9) extending circumferentially around an outer circumference of the frame 15 at or near the inflow end 11 to prevent paravalvular leakage of blood around the outside of the transcatheter heart valve prosthesis 10 once implanted in the patient.

[0049] FIGS. 3-4 show schematically side views of a delivery assembly 30 for delivering and deploying a transcatheter heart valve prosthesis (e.g., transcatheter heart valve prosthesis 10) according to aspects hereof. One skilled in the art will realize that FIGS. 3-4 illustrate one example of a delivery assembly 30 and that components illustrated in FIGS. 3-4 may be removed and / or additional components may be added. The delivery assembly 30 includes a proximal end 32, a distal end 31, and a handle 33. The handle 33 enables a physician to manipulate a distal portion of the delivery assembly 30 and includes actuators for moving parts of the delivery assembly 30 relative to other parts. In the delivery assembly 30, an outer shaft 34 is coupled to an actuator 39 of the handle 33 for moving the outer shaft 34 relative to an inner shaft 36.

[0050] A distal portion of the outer shaft 34, referred to as a capsule 35, is configured to surround a transcatheter heart valve prosthesis (e.g., transcatheter heart valve prosthesis 10) during delivery to the treatment site (e.g., a native heart valve) and is retracted from the transcatheter heart valve prosthesis to expose the transcatheter heart valve prosthesis such that it self-expands. The inner shaft 36 is coupled to the handle 33 and movement of the handle 33 translates to movement of the inner shaft 36 and a distal tip 37 (e.g., nosecone) coupled to a distal end of the inner shaft 36. The inner shaft 36 and distal tip 37 (e.g., nosecone) may also be translated relative to the outer shaft 34 and the handle 33 via a tip retractor. In the aspect shown, the inner shaft 36 includes a retainer 38 (e.g., spindle) for receiving the paddles of the transcatheter heart valve prosthesis 10.

[0051] When the actuator 39 is actuated, the actuator 39 moves the outer shaft 34 and the capsule 35 relative to the inner shaft 36, as shown in FIG. 4. As known to those skilled in the art,when the delivery assembly 30 is in position si is at the desired position at the treatment site in the patient’s vasculature, the actuator 39 is actuated to move the capsule 35 relative to the inner shaft 36 and the transcatheter heart valve prosthesis 10 disposed between the inner shaft 36 and the capsule 35, thereby enabling the transcatheter heart valve prosthesis 10 to deploy via self-expansion at the treatment site and release from the retainer 38, as shown in FIG. 4 (without showing the transcatheter heart valve prosthesis 10).

[0052] Minimally invasive percutaneous interventional procedures, including endovascular procedures, require access to the venous or arterial system. In general, it is desirable to make the smallest incision point with the shortest tissue contact time when entering the body. Small incisions and short tissue contact time generally lead to improved patient outcomes, less complications, and less trauma to the vessels or organs being accessed, as well as less trauma to the skin and tissue through which the access point is created. Access is required for various medical procedures that deliver or implant structural elements (such as heart valves, heart valve repair devices, occluders, grafts, electrical stimulators, leads, etc.) percutaneously. Some procedures employ relatively large devices that require relatively large sheaths to deliver the devices to the intended site within the body. With such procedures, access site trauma can occur, often resulting in vessel damage, excessive bleeding, increased case time, increased risk of infection, and increased hospitalization time. To reduce access trauma, physicians try to use the smallest devices possible and place the smallest sheath size. This can be problematic, however, if during the procedure the physician discovers a larger device is needed. This leads to a need to upsize the sheath, which is a lengthy procedure and leads to increased risk to the patient. Expandable sheaths can be expanded within the body and thus do not require removal to upsize.

[0053] Expandable sheath designs may be regionally or locally expansive to selectively and temporarily expand when the device is passing through a region of the sheath and to retract or recover when the device is not passing or has already passed through the sheath. Aspects disclosed herein may be employed with an expandable introducer sheath that may solve these and other issues that contribute to vascular trauma. The expandable introducer sheath disclosed herein is described with respect to percutaneous access for transcatheter heart valve repair or replacement, and it should be understood that one or more features of the expandable introducer sheath may be employed alone or in combination for other medical procedures requiring percutaneous access, including but not limited to placement of stents, angioplasty, removal of arterial or venous calcification, and pre-dilatation or post-dilatation.

[0054] Various aspects disclosed herein may include an introducer sheath that has a selectively expandable diameter to allow for the passage of a relatively larger devicetherethrough and further is configured to red device. The various aspects may reduce damage to surrounding tissues by reducing contact with those tissues and by eliminating the need to exchange sheaths of different sizes. As a result, in comparison to known sheaths, these aspects can reduce procedure time, vascular trauma, bleeding, and the resulting risk of infection and other complications. However, it should be understood that the present disclosure is not limited for use with an expandable introducer sheath. Rather, one or more features of the present disclosure can be employed either alone or in combination without an introducer sheath, with a non-expandable introducer sheath, or with an expandable introducer sheath. Likewise, if employed, the introducer sheath may be an integrated introducer sheath (e.g., an introducer sheath integrated with a delivery assembly) or a nonintegrated introducer sheath (e.g., an introducer sheath separate from the delivery assembly but provided for use with the delivery assembly).

[0055] FIGS. 5-6 depict an exemplary aspect of an introducer sheath 50 positioned through an incision 60 in the skin 65 of a patient and into a vessel 40 of a patient. The introducer sheath 50 has a tubular shaft 55 and a proximal hub 56 with a hemostatic seal and a luer lock 57. FIG. 5 shows the introducer sheath 50 positioned in the vessel 40 in its normal, unexpanded state, while FIG. 6 shows the introducer sheath 50 positioned in the vessel 40 with a delivery device 75 delivering another device 70 that is being advanced through the introducer sheath 50 such that the tubular shaft 55 expands or deforms at the location where the device 70 is passing through. The tubular shaft 55 expands at expanded region 58 when the device 70 passes through and then retracts or recovers to its original diameter after the device 70 moves past or is removed from the tubular shaft 55. Thus, the tubular shaft 55 is configured to be expandable and retractable.

[0056] In aspects, the expandability of the tubular shaft 55 (and any shaft described according to any aspect set forth herein) is achieved via the elasticity of the tubular shaft 55, which can result in the tubular shaft 55 being either self-expandable or self-expanding or mechanically expandable or mechanically expanding. For purposes of this application, selfexpandable means that the tubular shaft 55 is configured to expand to a predetermined or nominal diameter automatically (without any type of actuation, mechanical or otherwise). Further, for purposes of this application, mechanically expandable means that the tubular shaft 55 is configured to expand when a positionable medical device is positioned through the tubular shaft 55. That is, the device itself that is being passed through the tubular shaft 55 causes the expansion of the tubular shaft 55, as depicted in FIG. 6. Alternatively, the expandable characteristics of the shaft tubular can be caused by something other than elasticity.

[0057] After passage of the device, the retractable, or recoverable to its original, unexpanded state as depicted in FIG. 5. The retractability can be, in some aspects, achieved by the elasticity of the tubular shaft 55, which can result in the tubular shaft 55 being either self-retractable or self-retracting, self-recoverable, or self-contractable, or mechanically retractable or mechanically retracting, mechanically recoverable, or mechanically contractable. For purposes of this application, self-retractable means that the tubular shaft 55 is configured to retract to a predetermined or nominal diameter automatically (without any type of actuation, mechanical or otherwise). Further, for purposes of this application, mechanically retractable means that the tubular shaft 55 is configured to retract when a device or component is used to cause the tubular shaft 55 to retract or recover. Alternatively, the retractable characteristics of the tubular shaft 55 can be caused by something other than elasticity.

[0058] For purposes of this application, any device that can be positioned through an introducer sheath according to any aspect disclosed or contemplated herein can be referred to as a positionable medical device or insertable medical device. Such devices include guidewires, dilators, delivery devices (for delivery and / or placement of structural elements such as heart valves, heart valve repair devices, occluders, grafts, electrical stimulators, leads, etc.), guide catheters, guiding sheaths, diagnostic catheters, stent delivery systems, balloon catheters, and other known vascular devices. Other devices can include non-vascular devices such as scopes and other common surgical instruments. Further, the introducer sheath is configured to receive tissues or organs. Thus, as one non-limiting example, the introducer sheath 50 is described as being an expandable introducer sheath 50 for introduction of a delivery assembly 30 including a transcatheter heart valve prosthesis 10. In further examples, the introducer sheath 50 is employed for introduction of a catheter including an inflation apparatus for pre-dilatation or post-dilatation procedures.

[0059] FIGS. 7-8 explicitly show the sutures 723 and 801 and the skirts (e.g., inner skirt 711 and / or outer skirt 721) on the transcatheter heart valve prosthesis 10. For example, as discussed above and shown in FIG. 7, the at least one leaflet 21 can be attached to the frame 15 at the commissures 25 by the sutures 723. The at least one leaflet 21 can include a margin of attachment 701, where the sutures 723 attach the frame 15 the outer skirt 721, and / or the inner skirt 711, for example, forming a continuous outer surface 725 or inner surface 803 of the prosthetic valve 20 of bioprosthetic tissue. The leaflet 21, the outer skirt 721, and / or the inner skirt 711 can comprise bioprosthetic tissue. Also, as shown in the bottom view of FIG. 8, the inner surface 803 can comprise the inner skirt 711 attached to the frame 15 by a plurality of sutures 801 that can be the same or in addition to sutures 723 shown in FIG. 7.

[0060] FIG. 9 shows another aspect of or different as the transcatheter heart valve prosthesis 10 discussed above. The bioprosthetic device 901 includes an outflow end 912 (and an inlet end opposite the outflow end). As shown, a plurality of sutures 921 can attach a skirt 931 (that can generically correspond to the outer skirt 721 and / or the inner skirt 711 discussed above) to the frame 911. It is to be understood that the positioning and number of sutures of the plurality of sutures 921 can be different in further aspects without departing from the scope of the present disclosure. For example, the plurality of sutures 921 between the skirt 931 and the frame 911 can be independent of a location of any leaflets, for example, being substantially uniformly distributed over the skirt 931, concentrated at the ends of the skirt 931, or a combination thereof or in other arrangements entirely.

[0061] FIG. 15 schematically illustrates a portion of bioprosthetic tissue 1501 corresponding to a location where the bioprosthetic tissue 1501 is sutured (either directly or indirectly) to the frame. For example, with reference to FIGS. 2 and 7, the bioprosthetic tissue 1501 of FIG. 15 can correspond to a portion of the one or more leaflets 21 attached to the commissures 25 (e.g., by sutures 723). Additionally or alternatively, as shown in FIGS. 8-9, the bioprosthetic tissue 1501 of FIG. 15 can correspond to a location where the skirt (e.g., inner skirt 711, outer skirt 721, skirt 931) is attached to the frame 15 or 911. Also, as discussed above, the bioprosthetic tissue 1501 includes collagen (e.g., as fibrils 1241, 1243, 1231, and 1233 shown as triple helices of collagen fibers). As schematically shown by star 1535, fibrils 1231 and 1233 can be cross-linked to one another.

[0062] As shown in FIG. 15, an opening 1211 is defined by an inner periphery 1213 of the bioprosthetic tissue 1501, which is where a suture of the plurality of sutures can extend through (not shown for clarity) to attach the bioprosthetic tissue 1501 to a frame (e.g., directly or indirectly) of a bioprosthetic device. In aspects, a collagen cross-linking density at and / or near the inner periphery 1213 can be greater than a bulk collagen cross-linking density of the bulk of the bioprosthetic tissue 1501. In aspects, an elastic modulus and / or a shear modulus at and / or near the inner periphery 1213 can be greater than a corresponding elastic modulus and / or shear modulus of the bulk of the bioprosthetic tissue 1501. In aspects, an acoustic velocity of the bioprosthetic tissue 1501 at and / or near the inner periphery 1213 can be greater than a bulk acoustic velocity of the bulk of the bioprosthetic tissue 1501. Providing one or more of the properties (e.g., increased cross-linking density, increased elastic modulus, increased shear modulus, increased acoustic velocity) at and / or near a hole in the bioprosthetic tissue (e.g., corresponding to a location of a suture) can improve resistance of the bioprosthetic tissue and / or corresponding bioprosthetic device to suture pull-out.

[0063] As shown in FIG. 15, region 1: for a distance 1529 to the outer periphery 1521 of the region 1523 that can have different properties than a bulk of the bioprosthetic tissue 1501. In aspects, the distance 1529 can be 0.5 millimeters (mm) or more, 1.0 mm or more, 2 mm or more, 3 mm or less, 5 mm or more, 10 mm or less, 8 mm or less, 6 mm or less, 4 mm or less, or 2 mm or less. In aspects, the distance 1529 can be in a range from 0.5 mm to 10 mm, from 1.0 mm to 8 mm, from 2 mm to 6 mm, from 3 mm to 4 mm, or any range or subrange therebetween. As discussed above for the properties at and / or near, the inner periphery 1213, the region 1523 can have increased cross-linking density, increased elastic modulus, increased shear modulus, and / or increased acoustic velocity relative to a corresponding property of a bulk of the bioprosthetic tissue 1501. Additionally, in further aspects, as shown by the dashed boundary, an intermediate region 1551 between region 1523 and the rest of the bioprosthetic tissue 1501 (e.g., bulk) can have a cross-linking density, an elastic modulus, a shear modulus, and / or an acoustic velocity intermediate (i.e. between) the corresponding properties in region 1523 and in the bulk, although the intermediate region may not be present in other aspects.

[0064] Alternatively or additionally, there can be a smooth, continuous, and / or a stepwise increase in cross-linking density and / or mechanical properties through a plurality of adjacent regions. While FIG. 15 showed two regions (i.e., intermediate region 1551 extending to the outer periphery 1521 of the region 1523, and the region 1523), it is to be understood that this can extend to multiple regions with sequentially increasing crosslinking density and / or mechanical properties and / or a region having a gradient increase in crosslinking density and / or mechanical properties. As shown in FIG. 16, the bioprosthetic tissue 1601 and / or a collagen scaffold 1611 can have collagen fibrils 1603 with an increase in cross-linking density (e.g., cross link 1625 and / or mechanical properties heading in direction 1627. Depending on the method used to treat the bioprosthetic tissue and / or the collagen scaffold, the corresponding increase can be smooth and / or continuous. For example, the cross-linking density and / or mechanical properties can monotonically increase (i.e., alternatively increase and stay the same without decreasing) heading towards a maximal region (e.g., the predetermined location). In further aspects, the cross-linking density and / or the mechanical properties can continuously increase heading in direction 1627 towards predetermined location 1605. Alternatively, as shown, the cross-linking density and / or mechanical properties can have a more stepwise increase heading in direction 1627 toward predetermined location 1605 sequentially through different regions 1653, 1643, 1633, and 1623 (e.g., crossing boundaries indicated by dashed lines 1641, 1631, and 1621). The rate of increase in these increased properties can be constant, linear, exponential, polynomial, or follow some other relationship. As used here, the apparent increase in the increased cross-linking densityand / or mechanical properties will be referred t of relationship or type (e.g., continuous, stepwise) of the increase in the increased cross-linking density and / or mechanical properties. It is to be understood that this increasing gradient can be present in any of the locations or situations discussed herein (e.g., the one or more predetermined locations 1105, around opening 1211, etc.).

[0065] In aspects, the elastic modulus of the bioprosthetic tissue 1501 in region 1523 and / or at the inner periphery 1213 can be greater than the bulk elastic modulus by (a percentage of the bulk elastic modulus) 5% or more, 10% or more, 20% or more, 50% or more, 80% or more, 100% or more, 120% or more, 150% or more, 10,000% or less, 1,000% or less, 200% or less, 150% or less, 120% or less, 100% or less, 80% or less, or 60% or less. In aspects, the elastic modulus of the bioprosthetic tissue 1501 in region 1523 and / or at the inner periphery 1213 can be greater than the bulk elastic modulus by (a percentage of the bulk elastic modulus) from 5% to 10,000%, from 10% to 1,000%, from 20% to 200%, from 50% to 150%, from 80% to 120%, from 80% to 100%, or any range or subrange therebetween. Alternatively or additionally, the shear modulus and / or the acoustic velocity in region 1523 and / or at the inner periphery 1213 can be greater than the corresponding property in the bulk by (as a percentage of the corresponding property in the bulk) one more of the ranges discussed above in this paragraph. In aspects, a cross-linking density of the bioprosthetic tissue 1501 in region 1523 and / or at the inner periphery 1213 can be greater than the bulk cross-linking density by (a percentage of the bulk cross-linking density) 20% or more, 50% or more, 80% or more, 100% or more, 150% or more, 200% or more, 500% or more, 20,000% or less, 10,000% or less, 5,000% or less, 1,000% or less, 800% or less, 600% or less, 400% or less, or 200% or less. In aspects, a cross-linking density of the bioprosthetic tissue 1501 in region 1523 and / or at the inner periphery 1213 can be greater than the bulk cross-linking density by (a percentage of the bulk cross-linking density) from 20% to 20,000%, from 50% to 10,000%, from 80% to 5,000%, from 100% to 1,000%, from 150% to 800%, from 200% to 600%, from 200% to 400%, or any range or subrange therebetween.

[0066] In aspects, a portion of a surface area of the bioprosthetic tissue having the increased cross-linking density, increased elastic modulus, increased shear modulus, and / or increased acoustic velocity can be less than 50%, less than 30%, less than 25%, less than 20%, less than 15%, less than 10%, or less than 5%. Consequently, a majority of a surface area of the bioprosthetic tissue does not comprise the increased properties. In this way, the bioprosthetic tissue (e.g., of the bioprosthetic device) has the increased properties selectively located in a plurality of predetermined locations, for example, corresponding to locations of a plurality of sutures to provide increased suture retention.

[0067] Throughout the disclosure, “sut described (Gui et al., 2016, Biomaterials 102, 120-129), except that suture retention strength was evaluated by adding weights on a loop of a 5-0 Dyneema suture (DSM Biomedical) threaded through one side of the bioprosthetic tissue at a location cross-linked in accordance with the present disclosure, the location is 2 mm from the end, with force applied axially to the bioprosthetic tissue. The weights were augmented in 10 g increments until failure. Four replicates are conducted and the reported value is the mean of the replicates. As used herein, the load is reported based on the applied mass in grams, but is to be understood that actual force from the weights is in grams-force (gf), where 101.97 gf = 1 Newton. In aspects, the bioprosthetic device and / or the bioprosthetic tissue can exhibit a suture retention strength of 200 g or more, 220 g or more, 240 g or more, 260 g or more, 280 g or more, 300 g or more, 400 g or less, 350 g or less, 300 g or less, 280 g or less, or 250 g or less. In aspects, the bioprosthetic device and / or the bioprosthetic tissue can exhibit a suture retention strength from 200 g to 400 g, from 220 g to 350 g, from 240 g to 300 g, from 260 g to 300 g, or from 280 g to 300 g. In aspects, the suture retention strength measured at a location with the increased collagen cross-linking density can be greater than a suture retention strength measured at another location (without the increased collagen cross-linking density) by 20% or more, 50% or more, 100% or more, 200% or more, 1,000% or less, 500% or less, 250% or less, 150% or less, 100% or less, or 70% or less (e.g., from 20% to 1,000%, from 50% to 500%, from 100% to 250%, from 100% to 150%, or any range or subrange therebetween).

[0068] Methods of forming a bioprosthetic tissue and / or a bioprosthetic device by selectively cross-linking bioprosthetic tissue will now be discussed with reference to FIG. 10-15. As shown in FIG. 10, methods can comprise applying a cross-linking agent 1003 to one or more predetermined locations 1015 of a bioprosthetic tissue 1011 including collagen. In aspects, as shown, applying the cross-linking agent 1003 can comprise dispensing the cross-linking agent 1003 (e.g., a solution containing the cross-linking agent) from a container 1001 (e.g., micropipette, syringe). In further aspects, as shown, the cross-linking agent 1003 can be dispensed onto a surface 1013 of the bioprosthetic tissue at the one or more predetermined locations 1015, although the cross-linking agent can be applied by inserting the container (e.g., syringe) in the bioprosthetic tissue at the one or more predetermined locations. In aspects, the cross-linking agent 1003 can be activated by impinging the cross-linking agent with an optical wavelength that the cross-linking agent is sensitive to, which can cause cross-linking of the collagen in the bioprosthetic tissue. Exemplary aspects of the cross-linking agent 1003 include riboflavin, rose Bengal, eosin Y, or combinations thereof.

[0069] FIG. 11 illustrates a schematic10. As shown, the bioprosthetic tissue 1011 (e.g., surface 1013) includes a plurality of collagen fibrils 1101 and 1103. At the time when the cross-linking agent is applied, at least some of the collagen fibrils (e.g., collagen fibrils 1101 and 1103) may not be cross-linked. While there may be some crosslinks between collagen fibrils at the time when the cross-linking agent, the crosslinking density is low relative to the resulting cross-linking density at the predetermined location(s) at the end of methods.

[0070] In aspects, as shown in FIG. 12, methods can comprise stretching the bioprosthetic tissue 1201 in one or more directions, as indicated by arrows 1203 and / or 1205. The stretching can expose otherwise occluded (e.g., cryptic) locations where collagen can be cross-linked by the method. In further aspects, the stretching can occur during the applying the cross-linking agents. In further aspects, the stretching can occur (e.g., independently of the stretching occurring during the applying the cross-linking agent or continuing the stretching from during the applying the cross-linking agent) while the one or more predetermined locations 1015 is impinged by the light beam 1307, as discussed below with reference to FIG. 13). The light beam can be configured to impinge a region 1223 (e.g., bounded by dashed line 1221 corresponding to region 1523 in FIG. 15) around the opening 1211 corresponding to one or more of the predetermined locations.

[0071] As shown in FIG. 13, methods comprise cross-linking the collagen at the predetermined location 1015. As shown, the predetermined location 1015 is impinged with a light beam 1307 comprising an optical wavelength that the cross-linking agent 1003 is sensitive to. Impinging the predetermined location 1015 impinged with a light beam 1307 activates the cross-linking agent 1003 and results in cross-linking collagen at the predetermined location 1015 (e.g., see fibrils 1231 and 1233 cross-linked as indicated by star 1535 in region 1523 corresponding to one of the one or more predetermined locations). In aspects, the light beam 1307 can be generated by a light-emitting diode (LED) or a laser (e.g., laser diode) configured to emit a specific optical wavelength. In aspects, the light beam 1307 can comprise primarily or consist solely of wavelengths that will activate the cross-linking agent 1003. For example, riboflavin can be activated by UV-A light and / or blue light (e.g., from 360 nm to 450 nm) while rose Bengal and eosin Y can be activated by green light (e.g., from 500 nm to 570 nm, from 520 nm to 560 nm, 530±5 nm, or 560±5 nm). In further aspects, the light beam can primarily comprise and / or consist of light having an optical wavelength from 360 nm to 450 nm (e.g., from 370 nm to 430 nm, from 380 nm to 400 nm) or from 500 nm to 560 nm (e.g., from 520 nm to 540 nm, about 530 nm).

[0072] In aspects, as shown in FIG. 12 light source 1301 emitting the light beam 1307 and the bioprosthetic tissue 1011 having the one or more predetermined locations, where the photomask localizes the region impinged (and thus cross-linked) to the one or more predetermined locations by preventing additional light beam 1303 from impinging the surface 1013 of the bioprosthetic tissue 1011. In further aspects, the photomask 1305 can be a grayscale mask that allows limited intensity of the light beam around the periphery of a hole in the photomask 1305, which can generate an intermediate region (intermediate region 1551 in FIG. 15) with some cross-linking caused by the light beam but less cross-linking than closer to the center of the predetermined location 1015 (see region 1523). Alternatively, multiple impinging steps can occur with different photomasks used for each impinging step to form region 1523 and intermediate region 1551. In other aspects, there can be a relatively sharp transition in between the properties in region 1523 from the rest of the bioprosthetic tissue. As discussed above, an area corresponding to the one or more predetermined locations, where the cross-linking occurs during the impinging can be relatively limited (e.g., less than 30%, less than 25%, less than 20%, less than 15%, less than 10%, or less than 5%). Consequently, a majority of a surface area of the bioprosthetic tissue does not comprise the increased cross-linking density formed by the impinging. Alternatively, methods can impinge the predetermined location 1015 to induce photo-crosslinking at the predetermined location 1015 (but not other locations) without the use of a photomask through controlled application of the cross-linking agent 1003 to the predetermined location 1015 (with minimal or no spread of the cross-linking agent to other locations), for example using a syringe or micropipette to precisely dispense the cross-linking agent. It is to be understood that collagen cross-linking will not be induced by exposure to the light beam in the absence of the cross-linking agent to initiate the cross-linking reaction.

[0073] Additionally or alternatively, a gradient increase in cross-linking density and / or mechanical properties can be achieved (rather than just a single region with the increased crosslinking density and / or mechanical properties), as discussed herein with reference to FIGS. 15-16. In aspects, the gradient increase can be achieved by controlling the exposure of the bioprosthetic tissue (and / or collagen-containing scaffold) to the light beam. For example, as discussed in the previous paragraph, multiple photomasks and / or corresponding exposures can generate multiple regions having stepwise differences in cross-linking density and / or mechanical properties. Likewise, as also discussed in the previous paragraph, a grayscale mask (or other gradient mask) can be used to achieve a relatively continuous gradient increase in cross-linking density and / or mechanical properties. Also, the exposure time of the bioprosthetic tissue (and / or collagen- containing scaffold) to the light beam can be controlled by directing a narrow light beam. Forexample, a beam spot of the light beam can be and / or scanned a different number of times in different portions of the bioprosthetic tissue (and / or collagen-containing scaffold) to form the gradient increase in cross-linking density and / or mechanical properties, where a longer residence time (through changing the scan rate and / or through multiple scans) is expected to be associated with greater increases in cross-linking density and / or mechanical properties. Additionally or alternatively, different amounts of the cross-linking agent can be applied to corresponding regions of the bioprosthetic tissue (and / or collagen-containing scaffold) such that even a uniform exposure to the light beam would produce greater increases in cross-linking density and / or mechanical properties where there is more of the cross-linking agent. For example, multiple concentrations of the cross-linking agent can be used to apply higher concentrations of the cross-linking agent where higher cross-linking density and / or mechanical properties are to be formed; or a greater volume of the cross-linking agent can be applied in predetermined regions relative to other (e.g., an adjacent) region(s). It is to be understood that any of these options can be combined to form a predetermined gradient increase in cross-linking density and / or mechanical properties.

[0074] In aspects, as shown in FIG. 12, an opening 1211 can be formed in the bioprosthetic tissue 1201 at the one or more predetermined locations 1015 prior to the crosslinking (e.g., impinging the predetermined locations with the light beam). In further aspects, although not shown because sutures were omitted in FIGS. 12-15 for clarity, the one or more predetermined locations can be sutured (e.g., with a plurality of sutures extending through the corresponding plurality of holes - see opening 1211 in FIG. 12) before impinging the one or more predetermined locations with the light beam. Alternatively, the plurality of holes and / or the plurality of sutures can be formed at the corresponding one or more predetermined locations after impinging the one or more predetermined locations with the light beam. In any case, the suturing can attach the bioprosthetic tissue to a frame of the bioprosthetic device (either directly or indirectly). For example, as shown in FIG. 14, the bioprosthetic tissue 1401 can comprise collagen fibrils 1403 cross-linked (as indicated by star 1405), for example, at the one or more predetermined locations without an opening therein after it is impinged by the light beam, which can be subsequently sutured. In aspects, after the impinging the one or more predetermined locations with the light beam, the bioprosthetic tissue can be washed (e.g., with water or a buffer solution), for example, to remove excess, most of, or substantially all of the cross-linking agent from the bioprosthetic tissue.

[0075] In aspects, the one or more predetermined locations (e.g., regions of increased collagen cross-linking or other increased mechanical properties) can be in the one or more leaflets 21 that are attached (e.g., sutured) to the frame 15. In further aspects, the one or morepredetermined locations can be where the one the commissure 25. In further aspects, the one or more predetermined locations can be where the one or more leaflets 21 are attached to the frame 15 and / or a skirt (e.g., outer skirt 721 and / or inner skirt 711 in FIG. 7 and / or skirt 931 shown generally in FIG. 9) at a margin of attachment 701. In aspects, the one or more predetermined locations (e.g., regions of increased collagen cross-linking or other increased mechanical properties) can be in the one or more skirt(s) (e.g., outer skirt 721 and / or inner skirt 711 in FIG. 7 and / or skirt 931 shown generally in FIG. 9) that are attached (e.g., sutured) to the frame. In further aspects, the one or more predetermined locations in the one or more skirt(s) can be at a location separate from (e.g., independent from or distal from) the one or more leaflets. Alternatively or additionally, the one or more predetermined locations can include a free margin (e.g., edge) of the one or more leaflets (e.g., independent of where the leaflet is attached to the frame).

[0076] Additionally or alternatively, the predetermined location can be an outer periphery of a leaflet (e.g., the distal end of the leaflet furthest from the sutures 801 to the frame 15 - the portion shown closest to the center of FIG. 8). In further aspects, as discussed above with reference to FIG. 16, there can be a gradient increase in cross-linking density and / or mechanical properties heading towards this predetermined location. As discussed above, this gradient increase can be continuous or distributed between multiple adjacent regions in a step-wise manner. For example, with reference to FIGS. 8 and 16, the predetermined location 1605 (in FIG. 16) can correspond to the distal end (e.g., free margin) of the leaflet 21 (shown in FIG. 8), where the gradient increase occurs in direction 1627 (in FIG. 16) corresponding to a radial direction going from the sutures 801 towards the distal end (e.g., free margin) of the leaflet 21 (in FIG. 8). Additionally or alternatively, it is to be understood that the bioprosthetic issue (having the predetermined location with increased cross-linking density and / or mechanical properties - either from cells colonizing a collagen containing scaffold having such properties, as discussed below, or bioprosthetic issue treated according to method of the present disclosure) can be used independent from a frame as well as with a frame (as shown in FIGS. 1-2, 7-9, 12, and 15). For example, a bioprosthetic tissue in accordance with aspects of the present disclosure could be used as a leaflet in a bioprosthetic pulmonary valve that can be sutured into place without a frame.

[0077] Also, the above-mentioned methods can be applied to collagen-containing scaffolds to form a region having increased (and / or a gradient increase in) cross-linking density and / or mechanical properties. Forming a gradient increase in cross-linking density and / or mechanical properties can promote cell migration and / or colonization in the regions having the increased cross-linking density and / or mechanical properties. Without wishing to be bound by theory, an increase in cross-linking density of a collagen-containing scaffold is associated with anincrease in mechanical stiffness. Also, a regie gradient increase - associated with increased cross-linking density) adjacent to another region having relatively lower mechanical stiffness can promote cell migration and / or colonization in(to) the region with increased mechanical stiffness. Consequently, it is expected that providing the increase in mechanical stiffness through increased cross-linking density in accordance with aspects and methods of the present disclosure can lead to promote cell migration and / or colonization in(to) the region having increased cross-linking density. Further, providing a gradient increase can facilitate the migration of cells on the collagen-containing scaffold towards the predetermined location at the maximum of this gradient increase and / or subsequent colonization at or near the predetermined location having the maximum of the gradient increase since cells from a larger area will be able to sense this gradient increase and / or continue moving up the gradient increase than for a single region having substantially the same increased crosslinking density and / or mechanical properties (or for a collagen-containing scaffold without any region having increased cross-linking density and / or mechanical properties). For example, with reference to FIG. 16, cells can migrate in direction 1629 towards the predetermined location 1605 on the collagen-containing scaffold 1611, which can be the same as direction 1627 of the gradient increase. Consequently, a density of cells colonizing can be greater closer to the predetermined location 1605 than further from the predetermined location. Further, the increased migration of cells along the gradient increase and / or increased colonization at (or near) the maximum of the gradient increase can provide further increases in mechanical properties, biocompatibility, and / or longevity of the resulting material (e.g., bioprosthetic tissue formed from colonization of the collagen-containing scaffold). Indeed, bioprosthetic tissue can be formed by cell colonization of a collagen-containing scaffold having the gradient increase in cross-linking density and / or mechanical properties, where this gradient increase would still be present in the resulting bioprosthetic tissue.

[0078] The present disclosure provides bioprosthetic tissue (e.g., as part of a bioprosthetic device) with increased mechanical properties and / or cross-linking density of collagen at one or more predetermined locations as well as methods of making the same (e.g., selectively crosslinking the collagen in the bioprosthetic tissue). The one or more predetermined locations can correspond to locations where there are holes in the bioprosthetic tissue, for example, where the bioprosthetic tissue is sutured to the rest of the bioprosthetic device (e.g., frame). Providing increased cross-linking density, increased elastic modulus, increased shear modulus, and / or increased acoustic velocity at and / or near a hole in the bioprosthetic tissue (e.g., corresponding to a location of a suture) at the one or more predetermined locations relative to the corresponding properties of the bulk of the bioprosthetic tissue can improve resistance of the bioprosthetic tissueand / or corresponding bioprosthetic device to more predetermined locations with the increased properties can be surrounded by an intermediate region with properties intermediate between that at the one or more predetermined locations and the bulk of the bioprosthetic tissue, which can further improve resistance to suture pull-out, for example, by smoothing a transition between the properties at the one or more predetermined locations and the bulk of the bioprosthetic tissue. Providing the increased mechanical properties can enable the bioprosthetic tissue to closely mimic the properties of biological tissue in the bulk while improving the resistance to suture pull-out at the one or more predetermined locations corresponding to locations of a plurality of sutures. Also, methods of the present disclosure selectively cross-link collagen in the bioprosthetic tissue at the one or more predetermined by applying a cross-linking agent and then activating the cross-linking agent by impinging the crosslinking agent with an optical wavelength that the cross-linking agent is sensitive to.

[0079] Additionally or alternatively, a gradient increase (including smooth, continuous, and / or stepwise increase) in cross-linking density and / or mechanical properties can formed in a bioprosthetic tissue and / or a collagen-containing scaffold. Providing the gradient increase in cross-linking density and / or mechanical properties can facilitate migration of cells up the gradient increase of the collagen-containing scaffold and / or increased colonization of cells at or near the maximum of the gradient increase. Further, the increased migration of cells along the gradient increase and / or increased colonization at (or near) the maximum of the gradient increase can provide further increases in mechanical properties, biocompatibility, and / or longevity of the resulting material (e.g., bioprosthetic tissue formed from colonization of the collagen-containing scaffold). Indeed, bioprosthetic tissue can be formed by cell colonization of a collagen-containing scaffold having the gradient increase in cross-linking density and / or mechanical properties, where this gradient increase would still be present in the resulting bioprosthetic tissue.

[0080] In accordance with the disclosure, non-limiting aspects of the disclosure will now be described. Various combinations of the aspects can be provided in accordance with the disclosure.

[0081] Aspect 1. A bioprosthetic device comprises: a frame; a bioprosthetic tissue comprising collagen comprising a plurality of holes, the bioprosthetic tissue attached to the frame; and a plurality of sutures extending through the plurality of holes, wherein a periphery of the plurality of holes has a greater collagen cross-linking density than a bulk of the bioprosthetic tissue.

[0082] Aspect 2. The bioprosthetic devi a prosthetic heart valve assembly.

[0083] Aspect 3. The bioprosthetic device of any one of aspects 1-2, wherein the greater cross-linking density extends for a distance of from 0.5 mm to 10 mm from the periphery.

[0084] Aspect 4. The bioprosthetic device of any one of aspects 1-3, further comprising an intermediate region between the bulk of the bioprosthetic tissue and a peripheral region including the periphery of at least one of the plurality of holes with the greater collagen crosslinking density, wherein a cross-linking density of the intermediate region is between a crosslinking density of the bulk and the greater collagen cross-linking density of the peripheral region.

[0085] Aspect 5. A bioprosthetic device comprising: a frame; a bioprosthetic tissue comprising collagen comprising a plurality of holes, the bioprosthetic tissue attached to the frame; and a plurality of sutures extending through the plurality of holes, wherein a periphery of the plurality of holes has a greater elastic modulus than a bulk of the bioprosthetic tissue.

[0086] Aspect 6. The bioprosthetic device of aspect 5, wherein the periphery of the plurality of holes has a greater collagen cross-linking density than a bulk of the bioprosthetic tissue.

[0087] Aspect 7. The bioprosthetic device of any one of aspects 5-6, wherein the bioprosthetic device is a prosthetic heart valve assembly.

[0088] Aspect 8. The bioprosthetic device of any one of aspects 5-7, wherein the greater elastic modulus is greater than a bulk elastic modulus of the bulk of the bioprosthetic tissue by from 20% to 200% of the bulk elastic modulus.

[0089] Aspect 9. The bioprosthetic device of any one of aspects 5-8, wherein the greater cross-linking density extends for a distance of from 0.5 mm to 10 mm from the periphery.

[0090] Aspect 10. The bioprosthetic device of any one of aspects 5-9, wherein a suture retention strength of the bioprosthetic tissue is 200 g or more.

[0091] Aspect 11. A method of selectively cross-linking bioprosthetic tissue comprising: applying a cross-linking agent to one or more predetermined locations of the bioprosthetic tissue comprising collagen; and cross-linking collagen at the one or more predetermined locations by impinging the one or more predetermined locations with a light beam, the light beam comprises an optical wavelength that the cross-linking agent is sensitive to,wherein a majority of a surface area of 1 cross-linked by the impinging.

[0092] Aspect 12. The method of aspect 11, wherein the one or more predetermined locations corresponding to a location of one or more sutures in the bioprosthetic tissue.

[0093] Aspect 13. The method of any one of aspects 11-12, wherein the bioprosthetic tissue is part of a prosthetic heart valve assembly.

[0094] Aspect 14. The method of any one of aspects 11-13, wherein the cross-linking agent comprises riboflavin, rose Bengal, eosin Y, or combinations thereof.

[0095] Aspect 15. The method of any one of aspects 11-14, further comprising stretching the bioprosthetic tissue during the cross-linking.

[0096] Aspect 16. The method of any one of aspects 11-15, wherein the cross-linking further comprises positioning a photomask between a light source emitting the light beam and the one or more predetermined locations to localize the cross-linking to the one or more predetermined locations.

[0097] Aspect 17. The method of any one of aspects 11-16, further comprising, after the cross-linking, suturing the bioprosthetic tissue to form bioprosthetic device, wherein the suturing forms a plurality of sutures extending through a plurality of holes at one or more of the predetermined locations.

[0098] Aspect 18. The method of any one of aspects 11-16, further comprising, before the cross-linking, suturing the bioprosthetic tissue to form bioprosthetic device, wherein the suturing forms a plurality of sutures extending through a plurality of holes at one or more of the predetermined locations.

[0099] Aspect 19. The method of any one of aspects 17-18, wherein the bioprosthetic device is a prosthetic heart valve assembly.

[0100] Aspect 20. The method of any one of claims 11-19, wherein a suture retention strength of the bioprosthetic tissue is 200 g or more.

[0101] Aspect 21. The method of any one of aspects 11-20, wherein the light beam primarily comprises light of a wavelength that will activate the cross-linking agent.

[0102] Aspect 22. The method of any one of aspects 11-21, wherein the light beam primarily comprises light with an optical wavelength from 360 nanometers to 450 nm.

[0103] Aspect 23. The method of any one of aspects 11-21, wherein the light beam primarily comprises light with an optical wavelength from 500 nanometers to 570 nm.

[0104] Aspect 24. The method of any one of aspects 11-23, wherein the one or more predetermined locations comprises a margin of attachment of a leaflet.

[0105] Aspect 25. The method of an predetermined locations comprises a free margin of a leaflet.

[0106] Aspect 26. The method of any one of aspects, 11-25, wherein the one or more predetermined locations comprises a location where a skirt is attached to a frame.

[0107] Aspect 27. The bioprosthetic device of any one of aspects 1-10, wherein the one or more predetermined locations comprises a margin of attachment of a leaflet.

[0108] Aspect 28. The bioprosthetic device of any one of aspects 1-10, wherein the one or more predetermined locations comprises a free margin of a leaflet.

[0109] Aspect 29. The bioprosthetic device of any one of aspects 1-10, wherein the one or more predetermined locations comprises a location where a skirt is attached to a frame.

[0110] Aspect 30. A bioprosthetic device comprising a bioprosthetic tissue comprising collagen, wherein a predetermined location on the bioprosthetic tissue has a greater elastic modulus than an elastic modulus of a bulk of the bioprosthetic tissue.

[0111] Aspect 31. The bioprosthetic device of aspect 30, further comprising an intermediate region between the bulk of the bioprosthetic tissue and the predetermined location with the greater collagen cross-linking density, wherein an elastic modulus of the intermediate region is between the elastic modulus of the bulk and the greater elastic modulus at the predetermined location.

[0112] Aspect 32. The bioprosthetic device of any one of aspects 30-31, further comprising a gradient increase of the elastic modulus between the cross-linking density of the bulk of the bioprosthetic tissue and the elastic modulus at the predetermined location.

[0113] Aspect 33. A bioprosthetic device comprising a bioprosthetic tissue comprising, wherein a predetermined location on the bioprosthetic tissue has a greater collagen cross-linking density than a cross-linking density of the bulk of the bioprosthetic tissue.

[0114] Aspect 34. The bioprosthetic device of aspect 33, further comprising an intermediate region between the bulk of the bioprosthetic tissue and the predetermined location with the greater collagen cross-linking density, wherein a cross-linking density of the intermediate region is between the cross-linking density of the bulk and the greater collagen cross-linking density at the predetermined location.

[0115] Aspect 35. The bioprosthetic device of any one of aspects 33-34, further comprising a gradient increase of the cross-linking density between the cross-linking density of the bulk of the bioprosthetic tissue and the cross-linking density at the predetermined location.

[0116] Aspect 36. The bioprosthetic device of any one of aspects 30-35, wherein the bioprosthetic device is a prosthetic heart valve assembly.

[0117] Aspect 37. The bioprosthetic one or more predetermined locations comprises a margin of attachment of a leaflet.

[0118] Aspect 38. The bioprosthetic device of any one of aspects 30-35, wherein the one or more predetermined locations comprises a free margin of a leaflet.

[0119] Aspect 39. The bioprosthetic device of any one of aspects 30-38, wherein the bioprosthetic tissue further comprises a plurality of holes, the bioprosthetic device further comprising a plurality of sutures extending through the plurality of holes.

[0120] Aspect 40. The bioprosthetic device of aspect 39, further comprising a frame, wherein the bioprosthetic tissue is attached to the frame.

[0121] Aspect 41. A collagen-containing scaffold comprising a predetermined location having a greater collagen cross-linking density than a bulk of the collagen-containing scaffold.

[0122] Aspect 42. The collagen-containing scaffold of aspect 41, further comprising an intermediate region between the bulk and the predetermined location with the greater collagen cross-linking density, wherein a cross-linking density of the intermediate region is between the cross-linking density of the bulk and the greater collagen cross-linking density at the predetermined location.

[0123] Aspect 43. The collagen-containing scaffold of any one of aspects 41-42, further comprising a gradient increase of the cross-linking density between the cross-linking density of the bulk and the cross-linking density at the predetermined location.

[0124] Aspect 44. A collagen-containing scaffold comprising a predetermined location having a greater elastic modulus than a bulk of the collagen-containing scaffold due to a difference in collagen cross-linking between the predetermined location and the bulk.

[0125] Aspect 45. The collagen-containing scaffold of aspect 44, further comprising an intermediate region between the bulk and the predetermined location with the greater collagen cross-linking density, wherein an elastic modulus of the intermediate region is between the elastic modulus of the bulk and the greater elastic modulus at the predetermined location.

[0126] Aspect 46. The collagen-containing scaffold of any one of aspects 44-45, further comprising a gradient increase of the elastic modulus between the cross-linking density of the bulk and the elastic modulus at the predetermined location.

[0127] Aspect 47. A bioprosthetic device comprising the collagen-containing scaffold of any one of aspects 41-46 colonized by cells.

[0128] Aspect 48. The bioprosthetic device of aspect 47, wherein the bioprosthetic device is a prosthetic heart valve assembly.

[0129] Aspect 49. A method of selectively cross-linking a collagen-containing scaffold comprising:applying a cross-linking agent to one i containing scaffold; and cross-linking collagen at the one or more predetermined locations by impinging the one or more predetermined locations with a light beam, the light beam comprises an optical wavelength that the cross-linking agent is sensitive to, wherein a majority of a surface area of the collagen-containing scaffold does not comprise collagen cross-linked by the impinging.

[0130] Aspect 50. The method of aspect 49, wherein the cross-linking agent comprises riboflavin, rose Bengal, eosin Y, or combinations thereof.

[0131] Aspect 51. The method of any one of aspects 49-50, further comprising stretching the collagen-containing scaffold during the cross-linking.

[0132] Aspect 52. The method of any one of aspects 49-51, wherein the cross-linking further comprises positioning a photomask between a light source emitting the light beam and the one or more predetermined locations to localize the cross-linking to the one or more predetermined locations.

[0133] Aspect 53. The method of any one of aspects 49-52, wherein a residence time of the light beam on the collagen-containing scaffold increases closer to the predetermined location compared to a location on the collagen-containing scaffold further from the predetermined location.

[0134] Aspect 54. The method of any one of aspects 49-53, wherein an amount of the cross-linking agent on the collagen-containing scaffold increases closer to the predetermined location compared to a location on the collagen-containing scaffold further from the predetermined location.

[0135] Aspect 55. The method of any one of aspects 49-54, wherein the light beam primarily comprises light of a wavelength that will activate the cross-linking agent.

[0136] Aspect 56. The method of any one of aspects 49-55, further comprising, after the cross-linking, colonizing the collagen-containing scaffold with cells.

[0137] Aspect 57. The method of aspect 56, wherein a cell of the cells migrates towards the predetermined location.

[0138] Aspect 58. A bioprosthetic device comprising the collagen-containing scaffold colonized by cells produced by the method of any one of aspects 56-57.

[0139] Aspect 59. The bioprosthetic device of aspect 58, wherein the bioprosthetic device is a prosthetic heart valve assembly.

[0140] Aspect 60. The method of any one of aspects 58-59, wherein the one or more predetermined locations comprises a margin of attachment of a leaflet.

[0141] Aspect 61. The method of an predetermined locations comprises a free margin of a leaflet.

[0142] It should be understood that while various aspects have been described in detail relative to certain illustrative and specific examples thereof, the present disclosure should not be considered limited to such, as numerous modifications and combinations of the disclosed features are possible without departing from the scope of the following claims.

Claims

What is claimed is:

1. A bioprosthetic device comprising: a frame; a bioprosthetic tissue comprising collagen comprising a plurality of holes, the bioprosthetic tissue attached to the frame; and a plurality of sutures extending through the plurality of holes, wherein a periphery of the plurality of holes has a greater collagen cross-linking density than a bulk of the bioprosthetic tissue.

2. The bioprosthetic device of claim 1, wherein the bioprosthetic device is a prosthetic heart valve assembly.

3. The bioprosthetic device of any one of claims 1-2, wherein the greater cross-linking density extends for a distance of from 0.5 mm to 10 mm from the periphery.

4. The prosthetic device of any one of claims 1-3, further comprising an intermediate region between the bulk of the bioprosthetic tissue and a peripheral region including the periphery of at least one of the plurality of holes with the greater collagen cross-linking density, wherein a crosslinking density of the intermediate region is between a cross-linking density of the bulk and the greater collagen cross-linking density of the peripheral region.

5. A bioprosthetic device comprising: a frame; a bioprosthetic tissue comprising collagen comprising a plurality of holes, the bioprosthetic tissue attached to the frame; and a plurality of sutures extending through the plurality of holes, wherein a periphery of the plurality of holes has a greater elastic modulus than a bulk of the bioprosthetic tissue.

6. The bioprosthetic device of claim 5, wherein the periphery of the plurality of holes has a greater collagen cross-linking density than a bulk of the bioprosthetic tissue.

7. The bioprosthetic device of any one of claims 5-6, wherein the bioprosthetic device is a prosthetic heart valve assembly.

8. The bioprosthetic device of any one of claims 5-7, wherein the greater elastic modulus is greater than a bulk elastic modulus of the bulk of the bioprosthetic tissue by from 20% to 200% of the bulk elastic modulus.

9. The bioprosthetic device of any one of claims 5-8, wherein the greater cross-linking density extends for a distance of from 0.5 mm to 10 mm from the periphery.

10. The bioprosthetic device of any one of claims 5-9, wherein a suture retention strength of the bioprosthetic tissue is 200 g or more.

11. A method of selectively cross-linking bioprosthetic tissue comprising: applying a cross-linking agent to one or more predetermined locations of the bioprosthetic tissue comprising collagen; and cross-linking collagen at the one or more predetermined locations by impinging the one or more predetermined locations with a light beam, the light beam comprises an optical wavelength that the cross-linking agent is sensitive to, wherein a majority of a surface area of the bioprosthetic tissue does not comprise collagen cross-linked by the impinging.

12. The method of claim 11, wherein the one or more predetermined locations corresponding to a location of one or more sutures in the bioprosthetic tissue.

13. The method of any one of claims 11-12, wherein the bioprosthetic tissue is part of a prosthetic heart valve assembly.

14. The method of any one of claims 11-13, wherein the cross-linking agent comprises riboflavin, rose Bengal, eosin Y, or combinations thereof.

15. The method of any one of claims 11-14, further comprising stretching the bioprosthetic tissue during the cross-linking.

16. The method of any one of claims 11-15, wherein the cross-linking further comprises positioning a photomask between a light source emitting the light beam and the one or more predetermined locations to localize the cross-linking to the one or more predetermined locations.

17. The method of any one of claims 11-16, further comprising, after the cross-linking, suturing the bioprosthetic tissue to form bioprosthetic device, wherein the suturing forms a plurality of sutures extending through a plurality of holes at one or more of the predetermined locations.

18. The method of any one of claims 11-16, further comprising, before the cross-linking, suturing the bioprosthetic tissue to form bioprosthetic device, wherein the suturing forms a plurality of sutures extending through a plurality of holes at one or more of the predetermined locations.

19. The method of any one of claims 17-18, wherein the bioprosthetic device is a prosthetic heart valve assembly.

20. The method of any one of claims 11-19, wherein a suture retention strength of the bioprosthetic tissue is 200 g or more.

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